SRC-1 controls growth cone polarity and protrusion with the UNC-6/Netrin receptor UNC-5 in .

In the Polarity/Protusion model of growth cone migration away from the guidance cue UNC-6/Netrin, the UNC-5 receptor polarizes the VD growth cone such that filopodial protrusions are biased to the dorsal leading edge of the growth cone. UNC-5 also inhibits growth cone protrusion ventrally based upon this polarity. The SRC-1 tyrosine kinase has been previously shown to physically interact with and phosphorylate UNC-5, and to act with UNC-5 in axon guidance and cell migration. Here, the role of SRC-1 in VD growth cone polarity and protrusion is investigated. A precise deletion of was generated, and mutants displayed unpolarized growth cones with increased size, similar to mutants. Transgenic expression of in VD/DD neurons resulted in smaller growth cones, and rescued growth cone polarity defects of mutants, indicating cell-autonomous function. Transgenic expression of a putative kinase-dead mutant caused a phenotype similar to loss-of-function, suggesting that this is a dominant negative mutation. The D381A mutation was introduced into the endogenous gene by genome editing, which also had a dominant-negative effect. Genetic interactions of and suggest they act in the same pathway on growth cone polarity and protrusion, but might have overlapping, parallel functions in other aspects of axon guidance. function was not required for the effects of activated , suggesting that SRC-1 might be involved in UNC-5 dimerization and activation by UNC-6, of which is independent. In sum, these results show that SRC-1 acts with UNC-5 in growth cone polarity and inhibition of protrusion.